Abstracts from the 3rd International Severe Asthma Forum (ISAF)

Abstract

Introduction: Interleukin (IL)-17A plays a critical role in the pathogenesis of asthma. High levels of IL-17A are found in bronchial biopsies and serum obtained from patients with severe asthma. Deficiency of IL-17A signaling components attenuated airway inflammation in several mouse models of asthma. We recently identified a potent small molecule compound A18 (called cyanidin, a key pigment present in red berries and other fruits) for IL-17A inhibition through computeraided docking-based virtual screening. A18 specifically binds to a region in the IL-17RA extracellular domain that overlaps with the binding site for IL-17A and this binding potently disrupts the IL-17A/ IL-17RA complex. We demonstrated that cyanidin effectively inhibited IL-17A-mediated inflammatory gene expression in both human and mouse cells. In the current study, we further investigated if A18 could attenuated airway inflammation in mouse models of steroid-resistant and severe asthma. Method: Adoptive transfer models for antigen-induced airway inflammation OVA-specific Th17 and Th2 cells were transferred intravenously (i.v.) into WT C57BL/6 female mice. Mice were challenged (i.n.) with OVA323-339 1 day before transfer and 3 consecutive days after transfer. For A18 treatment, mice were injected (i.p.) with A18 on each challenge day. Measurements were performed 24 h after the last challenge. High-fat-diet (HFD) intervention Starting at 4 weeks of age, WT C57BL/6 male mice were fed with 10 kcal % fat chow diet (CD) or a 60 kcal % HFD for 14 weeks. A18 group of mice were injected (i.p.) with A18 daily for 4 weeks before subjection to measurements. House dust mite (HDM)-induced asthma WT C57BL/6 female mice were sensitized (s.c.) with HDM (100 μg/ mouse) in Complete Freund's Adjuvant on day 0 and subsequently challenged (i.n.) with HDM (100 μg/mouse) on day 14. A18 group of mice were injected (i.p.) with A18 on days 13 and 14 and also administrated (i.n.) with A18 1 h before challenging. Measurements were performed 24 h after the last challenge. Results: A18 inhibited Th17-induced but not Th2-induced airway inflammation. A18 substantially attenuated steroid-resistant obesity-associated asthma. A18 alleviated House dust mite (HDM)-induced neutrophilic airway inflammation. Conclusion: The findings strongly suggest that A18 (cyanidin) can be used as the prototype for developing small molecule drugs for treating the IL-17A-mediated severe asthma.